US3925451A - 13,14{86 -Methylene-15-oxoprostanoic acid derivatives - Google Patents

13,14{86 -Methylene-15-oxoprostanoic acid derivatives Download PDF

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Publication number
US3925451A
US3925451A US470050A US47005074A US3925451A US 3925451 A US3925451 A US 3925451A US 470050 A US470050 A US 470050A US 47005074 A US47005074 A US 47005074A US 3925451 A US3925451 A US 3925451A
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methylene
acid
reaction
oxoprostanoic
compound
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US470050A
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Kiyoshi Sakai
Kenji Inoue
Yawara Tajima
Mitsuo Yamazaki
Kazuo Ohuchi
Takashi Yusa
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Sankyo Co Ltd
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Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • ABSTRACT 13 l4tf-Methylene-l 5-oxoprostanoic acid derivative having the formula Dec. 9, 1975 A- COOR CH- CH-CHR CH OH wherein A, R and R are the same as above and, if desired, salifying the product thus obtained.
  • A represents a straight or branched alkylene group having from 4 to 8 carbon atoms
  • R represents a straight or branched alkyl group having from 4 to carbon atoms
  • R represents hydrogen atom or a straight or branched alkyl group having from one to 6 carbom atoms and pharmaceutically acceptable salts thereof and also relates to a process for the preparation thereof.
  • A may be a straight or branched alkylene group having from 4 to 8 carbon atoms, preferably, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, 4- methylhexamethylene, 4,4-dimethylhexamethylene, S-methylhexamethylene and 4-methylheptamethylene
  • R may be a straight or branched alkyl group having from 4 to 10 carbon atoms, preferably, n-butyl, isobutyl, n-pentyl, isopentyl, l-methylpentyl, 2-methylpentyl, l,l-dimethylpentyl, l,2-dimethylpentyl, n-hexyl, isohexyl, l-methylhexyl, l,l-dimethylhexyl, l,2-dimethylhexyl, n-heptyl, n-o
  • R may be hydrogen atom or a straight or branched alkyl group having from one to 6 carbom atoms, preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and n-hexyl.
  • Preferred groups of the prostanoic acid derivatives provided by the invention are those of the formula (I) wherein A represents hexamethylene group, i.e., those having the formula I I I I I wherein R' and R are the same as above and the pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts of the acids of formulae (1) and (l-a) in which R is hydrogen atom include alkali end alkaline earth metal salts, e.g., the sodium, potassium, magnesium and calcium salts, quaternary ammonium salts e.
  • the ammonium, tetramethylammonium, tetraethylammonium, benzyltrimethylammonium and phenyltriethylammonium salts aliphatic, alicyclic or aromatic amine salts, e.g., the methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylarnine, benzylamine, dibenzylamine, a-phenylethylamine and ethylenediamine salts, heterocyclic amine salts, e.g., the piperidine, morpholine, pyrrolidine, piperazine, pyridine, l-methylpiperazine and 4-ethylmorpholine salts, salts of amines which are water-soluble or contain a hydrophilic group, e.g., the monoethanolamine
  • the compound having the aforementioned general formula (I) prepared according to the process of the present invention for instance, dl-l3,l4 a-methylenel5-oxoprostanoic acid or dl-l 3,14 B-methylene-IS- oxoprostanoic acid, shows uncompetitive and strong inhibition against a prostaglandin-l5-OH dehydrogenase which is an enzyme quickly inactivating known prostaglandins in vivo.
  • the reaction was conducted at 45C by the use of 500 ml of a reaction solution which comprises 28 M of prostaglandin E 1.2 mM of nicotine-adenine dinucleotide (oxidation type), 1.0 mM of dithiothreitol, 40 mM of a potassium phosphate buffer solution (pH 7.3), a prostaglandin-IS-OH dehydrogenase obtained and purified from a lung of a pig and various concentrations of dl-l3,l4 a-methylene-IS- oxoprostanoic acid or dl-l3,l4 B-methylene-lS-oxoprostanoic acid. After 30 minutes the reaction was ceased by ice-cooling.
  • the present compounds may usually be dissolved with known prostaglandins in an isotonic sodium chloride solution and injected successively into a vein.
  • a does for adult per day may generally vary depending upon the amount of the known prostaglandins to be mixed, but may be between about l0 mg and mg.
  • the compound having the aforementioned general formula (I) can be prepared by oxidizing the compound having the general formula CH, OH
  • the reaction may be carried out in the presence or absence of a solvent by the use of an oxidizing agent.
  • the oxidizing agents to be employed may preferably be chromic acids such as chromic acid, chromic anhydride, a chromic anhydride-pyridine complex (Collins reagent), chromic anhydride-cone.
  • organic active halogen compounds such as N-bromoacetamide, N-bromosuccinimide, N- bromophthalimide, N-chloro-p-toluenesulfonamide and N-chlorobenzenesulfonamide; aluminum alkoxides such as aluminum tert-butoxide and aluminum isopropoxide, dimethylsulfoxide-dicyclohexylcarbodiimide, dimethylsulfoxide-acetic anhydride, dimethylsulfoxidechlorine-triethylamine and the like. An excess amount of the oxidizing agents may usually be employed.
  • the solvents to be employed in the case of using a solvent are not limited so far as these are inert to the present reaction and are preferably organic acids or mixture of organic acids and organic acid anhydrides such as, acetic acid and acetic acid-acetic anhydride or halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride in cases where chromic acids are employed. While, in cases where organic active halogen compounds are employed, aqueous organic solvents such as aqueous tert-butanol, aqueous acetone and aqueous pyridine are preferred. in cases where aluminum alkoxides are employed, aromatic hydrocarbons such as benzene, toluene and xylene are preferred.
  • chromic acids especially a chromic anhydride-pyridine complex (Collins reagent) and chromic anhydride-cone. sulfuric acid-water (Jones reagent), are employed as most preferred oxidizing agents.
  • the reaction temperature is not limited, but it is preferable to be relatively lower so as to avoid side reactions.
  • the reaction may be usually performed at a temperature from 20C to room temperature and preferably at a temperature from C to room temperature.
  • the reaction time may vary depending mainly upon the reaction temperature and the kind of oxidizing agents used and may be between about 10 minutes and l hour.
  • the desired compound is taken out of the reaction mixture in a usual way. For example, it is obtained by adding an organic solvent such as ether to the reaction mixture after the reaction is completed, removing the insoluble materials, washing and drying the resulting organic layer and evaporating the solvent from the organic layer.
  • the desired compound thus obtained may be further purified in a usual way, for example, column chromatography or thin layer chromatography, if required.
  • the compounds having the formula (I) wherein R is hydrogen atom may be alternatively obtained by hydrolyzing the compound having the formula (I) wherein R is the alkyl group.
  • the reaction may be achieved by bringing the compound having the formula (I) wherein R is the alkyl group into contact with an acid or base.
  • the acid or the base to be employed is unlimited one which may be used in a conventional hydrolysis, and may preferably be, for instance, a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid or a hydroxide of an alkali metal or an alkaline earth metal such as sodium hydroxide, potassium hydroxide or barium hydroxide, a carbonic acid salt of an alkali metal or an alkaline earth metal such as sodium carbonate, potassium carbonate or calcium carbonate.
  • the reaction may be conveniently carried out under basic conditions.
  • the reaction may be carried out in the presence or absence of a solvent.
  • the solvents to be employed are not limited so far as these are inert to the reaction, and preferably are, for instance, water and mixtures of water with alcohols such as methanol and ethanol or with others such as tetrahydrofuran and dioxane.
  • the reaction temperature is not specifically limited, but temperatures between room temperature and the reflux temperature may be preferred.
  • the compound having the aforementioned general formula (ll) which is employed as a starting material is a novel compound, and may be obtained by ring-formation to three-membered ring of the double bond of the compound having the general formula I I I I in which A, R and R have the same significance as defined above.
  • the reaction is carried out in the presence or absence of a solvent by bringing the compound (Ill) into contact with a reagent which is usually employed in the process of ring-formation to three-membered ring of a double bond.
  • a reagent which is usually employed in the process of ring-formation to three-membered ring of a double bond.
  • the reagents to be employed may be exemplified by zinc-containing metallic compoundmethylene dihalide such as diethyl zinc-methylene iodide, zinc powder-copper chloride-methylene iodide, zinc-copper-methylene iodide (Simmons-Smith reagent) or zinc (granular or powdery)-acetoxy silvermethylene iodide, diazomethane-zinc halide such as diazomethane-zinc iodide, benzyl methyl mercury iodide and dialkyl methyl aluminum iodide.
  • the solvents to be used may preferably be, for example, ether such as diethyl ether or diisopropyl ether or hydrocarbon such as hexane, cyclohexane or benzene.
  • the configuration of the three-membered ring of the starting compound having the aforementioned general formula (II) is affected by the configuration of the compound having the aforementioned general formula (III).
  • the compound having the three-membered ring of a-configuration is generally obtained in case the hydroxyl group of aconfiguration is employed.
  • the physical constants enough for determining whether the compound obtained in reference examples providing examples of the preparation of the starting compounds has the threemembered ring of a-configuration or that of B-configuration have not been yet obtained.
  • the ether layer was washed successively with a 2 aqueous sodium hydroxide solution, water, 2 N aqueous hydrochloric acid, water, a 3 aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. After evaporation of the solvent from the ether layer, there was obtained 0.99 g of an oil. The oil thus obtained was purified by means of column chromatography using silica gel to give 0.85 g of the desired compound as an oil.
  • EXAMPLE 4 dl- 1 3,14 B-Methylenel 5-oxoprostanoic acid COOH
  • 17 ml of anhydrous dichloromethane was dissolved 0.45 g of d1-13,l4 B-methylene-IS B-hydroxyprostanoic acid.
  • a mixture of 1.3 g of chromic anhydride, 2.1 ml of pyridine and 35 ml of dichloromethane was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was then treated in the same manner as in exanple 3 to give 0.28 g of the desired compound as white crystals, m.p. 49.5-51C.
  • reference examples 5 and 6 will illustrate the preparation of dl-13,14 a-methylene-lfi-oxoprostanoic acid from methyl dl-13,14 a-methylene-lS-oxoprostanoate and the preparation of d1-13,14 B-methylenel5-oxoprostanoic acid from methyl dl-13,l4 B-methylene- 1 S-oxoprostanoate.
  • E-Methylene-lS-oxoprostanoic acid derivatives having the formula wherein A represents a straight or branched alkylene group having from 4 to 8 carbon atoms, R represents a straight or branched alkyl group having from 4 to 10 carbon atoms and R represents hydrogen atom or a straight or branched alkyl group having from one to 6 carbon atoms and pharmaceutically acceptable salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US470050A 1973-06-02 1974-05-15 13,14{86 -Methylene-15-oxoprostanoic acid derivatives Expired - Lifetime US3925451A (en)

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JP48062122A JPS5012056A (fr) 1973-06-02 1973-06-02

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US (1) US3925451A (fr)
JP (1) JPS5012056A (fr)
BE (1) BE815907A (fr)
CA (1) CA1033728A (fr)
CH (1) CH609671A5 (fr)
DE (1) DE2426391A1 (fr)
FR (1) FR2231391B1 (fr)
GB (1) GB1425808A (fr)
NL (1) NL7407511A (fr)
SE (1) SE7407018L (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4742080A (en) * 1978-02-23 1988-05-03 Miles Laboratories, Inc. Therapeutic method for producing bronchodilation by administration of 15-deoxy-16-hydroxy prostaglandin esters

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3808259A (en) * 1971-09-09 1974-04-30 Sankyo Co 15-oxoprostanoic acid
US3842117A (en) * 1970-09-19 1974-10-15 Sankyo Co 15-oxoprost-13-enoic acid derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3842117A (en) * 1970-09-19 1974-10-15 Sankyo Co 15-oxoprost-13-enoic acid derivatives
US3808259A (en) * 1971-09-09 1974-04-30 Sankyo Co 15-oxoprostanoic acid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4742080A (en) * 1978-02-23 1988-05-03 Miles Laboratories, Inc. Therapeutic method for producing bronchodilation by administration of 15-deoxy-16-hydroxy prostaglandin esters

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Publication number Publication date
NL7407511A (fr) 1974-12-04
CA1033728A (fr) 1978-06-27
DE2426391A1 (de) 1975-01-02
BE815907A (fr) 1974-12-04
GB1425808A (en) 1976-02-18
JPS5012056A (fr) 1975-02-07
SE7407018L (fr) 1974-12-03
FR2231391A1 (fr) 1974-12-27
CH609671A5 (fr) 1979-03-15
FR2231391B1 (fr) 1978-07-21

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